scholarly journals Zebrafish Models of Photoreceptor Dysfunction and Degeneration

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 78
Author(s):  
Nicole C. L. Noel ◽  
Ian M. MacDonald ◽  
W. Ted Allison
Keyword(s):  
Usher Syndrome ◽  
Therapeutic Approaches ◽  
Instrumental System ◽  
Underlying Causes ◽  
Antisense Oligonucleotide Therapy ◽  
And Function ◽  
Therapeutic Compounds ◽  
Development Structure

Zebrafish are an instrumental system for the generation of photoreceptor degeneration models, which can be utilized to determine underlying causes of photoreceptor dysfunction and death, and for the analysis of potential therapeutic compounds, as well as the characterization of regenerative responses. We review the wealth of information from existing zebrafish models of photoreceptor disease, specifically as they relate to currently accepted taxonomic classes of human rod and cone disease. We also highlight that rich, detailed information can be derived from studying photoreceptor development, structure, and function, including behavioural assessments and in vivo imaging of zebrafish. Zebrafish models are available for a diversity of photoreceptor diseases, including cone dystrophies, which are challenging to recapitulate in nocturnal mammalian systems. Newly discovered models of photoreceptor disease and drusenoid deposit formation may not only provide important insights into pathogenesis of disease, but also potential therapeutic approaches. Zebrafish have already shown their use in providing pre-clinical data prior to testing genetic therapies in clinical trials, such as antisense oligonucleotide therapy for Usher syndrome.

Functional characterization of human brown adipose tissue metabolism

2020 ◽  
Vol 477 (7) ◽  
pp. 1261-1286 ◽  
Author(s):  
Marie Anne Richard ◽  
Hannah Pallubinsky ◽  
Denis P. Blondin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Functional Characterization ◽  
Human Infants ◽  
Positron Emission ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

scholarly journals miR-135a Reduces Osteosarcoma Pulmonary Metastasis by Targeting Both BMI1 and KLF4

2021 ◽  
Vol 11 ◽  
Author(s):  
Chenglong Chen ◽  
Xingjia Mao ◽  
Caitong Cheng ◽  
Yurui Jiao ◽  
Yi Zhou ◽  
...  
Keyword(s):  
Cell Invasion ◽  
Tumor Recurrence ◽  
Response Rate ◽  
Ectopic Expression ◽  
Chemotherapy Treatment ◽  
Therapeutic Approaches ◽  
Inhibit Tumor Growth ◽  
And Function ◽  
Novel Therapeutic

Because of the modest response rate after surgery and chemotherapy, treatment of osteosarcoma (OS) remains challenging due to tumor recurrence and metastasis. miR-135a has been reported to act as an anticarcinogenic regulator of several cancers. However, its expression and function in osteosarcoma remain largely unknown. Here, we reported that abridged miR-135a expression in OS cells and tissues, and its expression is inversely correlated with the expression of BMI1 and KLF4, which are described as oncogenes in several cancers. Ectopic expression of miR-135a inhibited cell invasion and expression of BMI1 and KLF4 in OS cells. In vivo investigation confirmed that miR-135a acts as a tumor suppressor in OS to inhibit tumor growth and lung metastasis in xenograft nude mice. BMI1 and KLF4 were revealed to be direct targets of miR-135a, and miR-135a had a similar effect as the combination of si-BMI1 and si-KLF4 on inhibiting tumor progression and the expression of BMI1 and KLF4 in vivo. Altogether, our results demonstrate that the targeting of BMI1/KLF4 with miR-135a may provide an applicable strategy for exploring novel therapeutic approaches for OS.

scholarly journals Nanomechanics and co-transcriptional folding of Spinach and Mango

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jaba Mitra ◽  
Taekjip Ha
Keyword(s):  
Single Molecule ◽  
Rna Aptamers ◽  
Biophysical Characterization ◽  
Mechanical Responses ◽  
Discrete Step ◽  
Force Relaxation ◽  
G Quadruplex ◽  
And Function

Abstract Recent advances in fluorogen-binding “light-up” RNA aptamers have enabled protein-free detection of RNA in cells. Detailed biophysical characterization of folding of G-Quadruplex (GQ)-based light-up aptamers such as Spinach, Mango and Corn is still lacking despite the potential implications on their folding and function. In this work we employ single-molecule fluorescence-force spectroscopy to examine mechanical responses of Spinach2, iMangoIII and MangoIV. Spinach2 unfolds in four discrete steps as force is increased to 7 pN and refolds in reciprocal steps upon force relaxation. In contrast, GQ-core unfolding in iMangoIII and MangoIV occurs in one discrete step at forces >10 pN and refolding occurred at lower forces showing hysteresis. Co-transcriptional folding using superhelicases shows reduced misfolding propensity and allowed a folding pathway different from refolding. Under physiologically relevant pico-Newton levels of force, these aptamers may unfold in vivo and subsequently misfold. Understanding of the dynamics of RNA aptamers will aid engineering of improved fluorogenic modules for cellular applications.

scholarly journals Extracellular vesicles: Exosomes, microvesicles, and friends

2013 ◽  
Vol 200 (4) ◽  
pp. 373-383 ◽  
Author(s):  
Graça Raposo ◽  
Willem Stoorvogel
Keyword(s):  
Plasma Membrane ◽  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Membrane Vesicles ◽  
Vesicle Release ◽  
Physiological Relevance ◽  
And Function ◽  
Extracellular Environment

Cells release into the extracellular environment diverse types of membrane vesicles of endosomal and plasma membrane origin called exosomes and microvesicles, respectively. These extracellular vesicles (EVs) represent an important mode of intercellular communication by serving as vehicles for transfer between cells of membrane and cytosolic proteins, lipids, and RNA. Deficiencies in our knowledge of the molecular mechanisms for EV formation and lack of methods to interfere with the packaging of cargo or with vesicle release, however, still hamper identification of their physiological relevance in vivo. In this review, we focus on the characterization of EVs and on currently proposed mechanisms for their formation, targeting, and function.

Structure and function of the plasminogen/plasmin system

2005 ◽  
Vol 93 (04) ◽  
pp. 647-654 ◽  
Author(s):  
Victoria Ploplis ◽  
Francis Castellino
Keyword(s):  
Structure And Function ◽  
Human Condition ◽  
Matrix Proteins ◽  
Tissue Type ◽  
Type Plasminogen Activator ◽  
Vascular Patency ◽  
And Function ◽  
Deficient Mice

SummaryActivation of the fibrinolytic system is dependent on the conversion of the plasma zymogen, plasminogen (Pg), to the serine protease plasmin (Pm) by the physiological activators urokinase-type Pg activator (uPA) or tissue-type plasminogen activator (tPA). The primary in vivo function of Pm is to regulate vascular patency by degrading fibrin-containing thrombi. However, the identification of Pg/Pm receptors and the ability of Pm to degrade other matrix proteins have implicated Pm in other functions involving degradation of protein barriers, thereby mediating cell migration, an important event in a number of normal e.g., embryogenesis, wound healing, angiogenesis, and pathological, e.g., tumor growth and dissemination, processes. Prior to the development of Pg-deficient mice, much of the evidence for its role in other biological events was based on indirect studies. With the development and characterization of these mice, and ability to apply challenges utilizing a number of animal models that mimic the human condition, a clearer delineation of Pg/Pm function has evolved and has contributed to an understanding of mechanisms associated with a number of pathophysiological events.

scholarly journals Functional and Antigenic Characterization of Human, Rhesus Macaque, Pigtailed Macaque, and Murine DC-SIGN

2001 ◽  
Vol 75 (21) ◽  
pp. 10281-10289 ◽  
Author(s):  
Frédéric Baribaud ◽  
Stefan Pöhlmann ◽  
Tim Sparwasser ◽  
Monica T. Yu Kimata ◽  
Yang-Kyu Choi ◽  
...  
Keyword(s):  
Rhesus Macaque ◽  
Lectin Binding ◽  
Binding Domain ◽  
Repeat Region ◽  
Mucosal Tissues ◽  
C Terminus ◽  
Antigenic Characterization ◽  
And Function

ABSTRACT DC-SIGN, a type II membrane protein with a C-type lectin binding domain that is highly expressed on mucosal dendritic cells (DCs) and certain macrophages in vivo, binds to ICAM-3, ICAM-2, and human and simian immunodeficiency viruses (HIV and SIV). Virus captured by DC-SIGN can be presented to T cells, resulting in efficient virus infection, perhaps representing a mechanism by which virus can be ferried via normal DC trafficking from mucosal tissues to lymphoid organs in vivo. To develop reagents needed to characterize the expression and in vivo functions of DC-SIGN, we cloned, expressed, and analyzed rhesus macaque, pigtailed macaque, and murine DC-SIGN and made a panel of monoclonal antibodies (MAbs) to human DC-SIGN. Rhesus and pigtailed macaque DC-SIGN proteins were highly similar to human DC-SIGN and bound and transmitted HIV type 1 (HIV-1), HIV-2, and SIV to receptor-positive cells. In contrast, while competent to bind virus, murine DC-SIGN did not transmit virus to receptor-positive cells under the conditions tested. Thus, mere binding of virus to a C-type lectin does not necessarily mean that transmission will occur. The murine and macaque DC-SIGN molecules all bound ICAM-3. We mapped the determinants recognized by a panel of 16 MAbs to the repeat region, the lectin binding domain, and the extreme C terminus of DC-SIGN. One MAb was specific for DC-SIGN, failing to cross-react with DC-SIGNR. Most MAbs cross-reacted with rhesus and pigtailed macaque DC-SIGN, although none recognized murine DC-SIGN. Fifteen of the MAbs recognized DC-SIGN on DCs, with MAbs to the repeat region generally reacting most strongly. We conclude that rhesus and pigtailed macaque DC-SIGN proteins are structurally and functionally similar to human DC-SIGN and that the reagents that we have developed will make it possible to study the expression and function of this molecule in vivo.

scholarly journals Characterization of Phosphopantetheinyl Hydrolase from Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Shilpika Pandey ◽  
Amrita Singh ◽  
Guangli Yang ◽  
Felipe B. d’Andrea ◽  
Xiuju Jiang ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Cell Wall ◽  
Mycobacterium Tuberculosis ◽  
Posttranslational Modification ◽  
Content Type ◽  
Protein Encoding ◽  
And Function ◽  
Encoding Genes

Tuberculosis (TB), caused by Mycobacterium tuberculosis , was the leading cause of death from an infectious disease before COVID, yet the in vivo essentiality and function of many of the protein-encoding genes expressed by M. tuberculosis are not known. We biochemically characterize M. tuberculosis ’s phosphopantetheinyl hydrolase, PptH, a protein unique to mycobacteria that removes an essential posttranslational modification on proteins involved in synthesis of lipids important for the bacterium’s cell wall and virulence.

scholarly journals Copper binding by a unique family of metalloproteins is dependent on kynurenine formation

2021 ◽  
Vol 118 (23) ◽  
pp. e2100680118
Author(s):  
Anastasia C. Manesis ◽  
Richard J. Jodts ◽  
Brian M. Hoffman ◽  
Amy C. Rosenzweig
Keyword(s):  
Biochemical Characterization ◽  
Protein A ◽  
Copper Ion ◽  
Copper Homeostasis ◽  
Metabolic Enzyme ◽  
Copper Binding ◽  
Methane Oxidizing Bacteria ◽  
And Function

Some methane-oxidizing bacteria use the ribosomally synthesized, posttranslationally modified natural product methanobactin (Mbn) to acquire copper for their primary metabolic enzyme, particulate methane monooxygenase. The operons encoding the machinery to biosynthesize and transport Mbns typically include genes for two proteins, MbnH and MbnP, which are also found as a pair in other genomic contexts related to copper homeostasis. While the MbnH protein, a member of the bacterial diheme cytochrome c peroxidase (bCcP)/MauG superfamily, has been characterized, the structure and function of MbnP, the relationship between the two proteins, and their role in copper homeostasis remain unclear. Biochemical characterization of MbnP from the methanotroph Methylosinus trichosporium OB3b now reveals that MbnP binds a single copper ion, present in the +1 oxidation state, with high affinity. Copper binding to MbnP in vivo is dependent on oxidation of the first tryptophan in a conserved WxW motif to a kynurenine, a transformation that occurs through an interaction of MbnH with MbnP. The 2.04-Å-resolution crystal structure of MbnP reveals a unique fold and an unusual copper-binding site involving a histidine, a methionine, a solvent ligand, and the kynurenine. Although the kynurenine residue may not serve as a CuI primary-sphere ligand, being positioned ∼2.9 Å away from the CuI ion, its presence is required for copper binding. Genomic neighborhood analysis indicates that MbnP proteins, and by extension kynurenine-containing copper sites, are widespread and may play diverse roles in microbial copper homeostasis.

scholarly journals The nuclear factor-kappaB (NF-kappaB): from a versatile transcription factor to a ubiquitous therapeutic target.

2006 ◽  
Vol 53 (4) ◽  
pp. 651-662 ◽  
Author(s):  
Laura L Yates ◽  
Dariusz C Górecki
Keyword(s):  
Nuclear Factor Kappab ◽  
Specific Response ◽  
Nuclear Factor ◽  
Therapeutic Approaches ◽  
Altered Regulation ◽  
Nf Kappab ◽  
Novel Therapeutic Strategies ◽  
And Function

The nuclear factor-kappaB (NF-kappaB) transcription factors regulate a plethora of cellular pathways and processes including the immune response, inflammation, proliferation, apoptosis and calcium homeostasis. In addition to the complexity of its physiological roles, the composition and function of this family of proteins is very complicated. While the basic understanding of NF-kappaB signalling is extensive, relatively little is know of the in vivo dynamics of this pathway or what controls the balance between various outcomes. Although we know a large number of NF-kappaB-responsive genes, the contribution of these genes to a specific response is not always clear. Finally, the involvement of NF-kappaB in pathological processes is only now beginning to be unravelled. In addition to cancer and immunodeficiency disorders, altered regulation of NF-kappaB has been associated with several inherited diseases. These findings indicate that modulation of the NF-kappaB pathways may be beneficial. However, our limited knowledge of NF-kappaB signalling hinders therapeutic approaches: in many situations it is not clear whether the enhancement or inhibition of NF-kappaB activity would be beneficial or which pathways to interfere with and what the required level of activation is. Further studies of the role of NF-kappaB are needed as these may result in novel therapeutic strategies for a wide variety of diseases.

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